The overall goal of this PPG is to understand the genetic, genomic, and epigenetic determinants of variable susceptibility to develop COPD. Three COPD susceptibility loci have recently been definitively identified by genome-wide association studiestwo loci on chromosome 4 (near HHIP and in FAM13A) and one locus on chromosome 15 (a block of genes including IREB2). However, the key genetic determinants in these regions and their functional impact on COPD have not been defined. The three projects In this PPG focus on Genetics (Project 1, PI: Silverman); Gene Expression (Project 2, PI: Choi); and DNA Methylation (Project 3, PI: DeMeo). These projects will build on a substantial existing infrastructure of well-phenotyped study populations, experience in phenotypic characterization of COPD, and an extensive track record of both in vitro and in vivo functional assessment of COPD pathogenesis. There are likely multiple additional COPD susceptibility loci, which need to be discovered. Some of these genetic loci may be influenced primarily by epigenetic alterations (e.g. DNA methylation) instead of, or In addition to, heritable SNP variation. Moreover, the other gene members of the pathways related to these genetic determinants of COPD are unknown, and assessment of gene expression and DNA methylation can likely provide insight into these pathways. Thus, we have included Discovery of additional gene expression and epigenetic influences on COPD susceptibility as a central focus of this PPG. In addition, the actual genetic determinants within the GWAS loci have not been proven. Thus, we have included efforts to localize the key genes within those regions. Multiple approaches will be used to accomplish this goal. Including assessment of genetic association in a population of different genetic ancestry (African Americans from the COPDGene project), analysis of gene expression among genes within GWAS loci, assessment for epigenetic changes of genes within GWAS loci, and assays of long-range gene regulation (e.g. chromosome conformation capture). In addition to Localization of the key determinants, Functional Validation will be required to confirm that specific genes are Involved in COPD pathogenesis and to understand their impact. We will employ both in vitro assessment within lung epithelial and monocyte cell lines (with validation in primary cell types) as well as in vivo assessment in murine models of underexpression (knockout) of the key genes and susceptible vs. resistant Inbred strains which are tested with long-term cigarette smoke exposure. We anticipate that these studies will provide insight into the pathways and mechanisms for COPD susceptibility.